The present invention relates to a pharmaceutical composition comprising as an active agent an inhibitor of HER3 activity, particularly an anti-HER3-antibody. Further, the use of this composition for the diagnosis, prevention or treatment of hyperproliferative diseases, particularly tumor diseases is disclosed.
Protein tyrosine kinases are known to be enzymes, which mediate signal transduction processes that regulate cell growth and differentiation. Receptor protein tyrosine kinases act via ligand-stimulated tyrosine phosphorylation of substrates. HER3 (also called ErbB3) is a member of the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases (Plowman et al., Proc. Natl. Acad. Sci. U.S.A. 87 (1990), 4905-4909; Kraus et al., Proc. Natl. Acad. Sci. U.S.A. 86 (1989), 9193-9197 and Kraus et al., Proc. Natl. Acad. Sci. U.S.A. 90 (1993), 2900-2904).
HER3 has been found to be overexpressed in several types of cancer such as breast, gastrointestinal and pancreatic cancers. When HER3 is co-expressed with HER2, another member of the EGFR subfamily of receptor protein tyrosine kinases, an active heterodimeric signalling complex is formed.
A monoclonal antibody against HER3 (Rajkumar. et al., Br. J. Cancer 70 (1994), 459-456) had an agonistic effect on the anchorage-independent growth of cell lines expressing HER3. On the other hand, anti-HER3 antibodies described in U.S. Pat. No. 5,968,511 (corresponding to WO 97/35885) are reported to reduce Heregulin-induced formation of HER2/HER3 heterodimers. Such an activity, however, is only demonstrated for an antibody which increases Heregulin binding to HER3. Thus, it is not clear which type of anti-HER3-antibody—if any—has potential of being used for therapeutic applications.
Vadlamudi et al. (Oncogenes 18 (1999), 305-314) describe the regulation of the cyclooxygenase (COX-2) pathway by the HER2 receptor. It was found that a specific inhibitor of COX-2 can suppress the mitogenic and invasive action of colorectal cancer cells. Further, it was found that incubation with a monoclonal anti-HER3 antibody leads to a reduction in the levels HER2/HER3 heterodimers, but results in an only partial reduction of COX-2 expression.
WO 00/31048 discloses a quinazoline derivative which acts as an inhibitor of receptor tyrosine kinases such as EGFR, HER2 and HER4. An inhibition of HER3 is however not disclosed.
WO 00/78347 discloses methods for arresting or inhibiting cell growth, comprising preventing or reducing ErbB-2/ErbB-3 heterodimer formation. For example, the agent may be a combination of an anti-HER2 extracellular domaine antibody and an anti-HER3 antibody, e.g. the HER3 antibody H3.105.5 purchased from Neomarkers. It is however not clear which type of anti-HER3 antibody is required to obtain desirable therapeutic effects.
U.S. Pat. No. 5,804,396 describes a method for identifying an agent for treatment of a proliferative disorder, comprising the steps of assaying a potential agent for activity in inhibition of signal transduction by a HER2/HER3 or HER2/HER4 or HER3/HER4 heterodimer. Specific HER3 inhibitors are not disclosed.